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Trial registered on ANZCTR


Registration number
ACTRN12615001143516
Ethics application status
Approved
Date submitted
15/10/2015
Date registered
28/10/2015
Date last updated
27/06/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A first in human study assessing the safety and pharmacokinetics (blood levels) of RA101495.
Scientific title
A Phase I, Randomized, Placebo-Controlled, Double-Blind, Single Dose, Escalating Dose and Multiple-Dose Study of the Safety and Pharmacokinetics of RA101495 in Healthy Volunteers
Secondary ID [1] 287633 0
RA101495-1001
Universal Trial Number (UTN)
Trial acronym
N/A
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Paroxysmal nocturnal hemoglobinuria 296452 0
Condition category
Condition code
Blood 296712 296712 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Up to 5 cohorts of healthy volunteers will be defined by escalating dose of RA101495.
Cohort 1: 0.05 mg/kg single subcutaneous injection of RA101495 or placebo
Cohort 2: 0.10 mg/kg single subcutaneous injection of RA101495 or placebo
Cohort 3: 0.20 mg/kg single subcutaneous injection of RA101495 or placebo
Cohort 4: 0.40 mg/kg single subcutaneous injection of RA101495 or placebo
Cohort 5: 0.80 mg/kg single subcutaneous injection of RA101495 or placebo

Each subject will receive only one dose of study drug as a subcutaneous injection on Day 1 while in the clinic.

Subsequently, Up to 2 cohorts of healthy volunteers will be administered:
Cohort 6: 0.20 mg/kg once daily for 7 days subcutaneous injection of RA101495 or placebo
Cohort 7: 0.40 mg/kg once daily for 7 days subcutaneous injection of RA101495 or placebo
Intervention code [1] 293033 0
Treatment: Drugs
Comparator / control treatment
Placebo (50 mM sodium phosphate and 100 mM sodium chloride)
Control group
Placebo

Outcomes
Primary outcome [1] 296323 0
The safety and tolerability of a single dose of RA101495.

Safety will be monitored by adverse event reporting, clinical laboratory tests, electrocardiograms, vital signs, and physical examinations.
This study is the first time RA101495 is given to people and the side effects are not known.
Timepoint [1] 296323 0
Screening, Day 1 (pre-dose; 15 minutes; 1, 3, 6, 12 hours post dose), Day 2, 3, 5, 8, 15, 29.
Primary outcome [2] 297293 0
The safety and tolerability of a multiple doses of RA101495 administered once daily for 7
days.

Safety will be monitored by adverse event reporting, clinical laboratory tests, electrocardiograms, vital signs, and physical examinations. This study is the first time RA101495 is given to people and the side effects are not known.
Timepoint [2] 297293 0
Multiple Dose: Screening, Day 1-7 (pre-dose; 3, 6 hours post dose), Day 8, 15, 21, 35.
Secondary outcome [1] 318148 0
Pharmacokinetics of RA101495, including:
*Area under the drug concentration-time curve from time 0 to infinity (AUC0-inf)
*Area under the drug concentration-time curve from time 0 to the last quantifiable timepoint (AUC0-t)
*Maximum observed concentration (Cmax)
*Time corresponding to Cmax (tmax)
Timepoint [1] 318148 0
Single Dose: Day 1 (pre-dose; 15 minutes; 1, 3, 6, 12 hours post dose), Day 2, 3, 5, 8, 15, 29.

Multiple Dose: Day 1-7 (pre-dose; 3, 6 hours post dose), Day 8, 15, 21, 35.
Secondary outcome [2] 318149 0
Effect of RA101495 on complement activity
Blood samples will be collected and sent to a certified laboratory for analysis. Tests will include 1)CH50 to measures the amount of plasma required to lyse 50% of RBCs in the assay mixture; 2) assay for red blood cell lysis to measure complement activity by determining what percent of RBCs are lysed after incubation with plasma sample; 3) Weislab ELISA to measure activity of the alternative complement pathway by measuring the amount of complement components C5b-C9 present in the plasma sample; 4) C5 ELISA to measures the amount of complement component C5 present in the plasma sample.
Timepoint [2] 318149 0
Single Dose: Screening, Day 1 (pre-dose; 15 minutes; 1, 3, 6, 12 hours post dose), Day 2, 3, 5, 8, 15, 29.

Multiple Dose: Screening, Day 1-7 (pre-dose; 3, 6 hours post dose), Day 8, 15, 21, 35.
Secondary outcome [3] 318150 0
Presence or absence of antibodies against RA101495
Blood samples for anti-drug antibodies will be sent to a certified laboratory to determine the presence or absence of antibodies against RA101495, using a validated assay.
Timepoint [3] 318150 0
Single Dose: Day 1 (pre-dose), Day 8, 15, 29.

Multiple Dose: Day 1 (pre-dose), Day 35
Secondary outcome [4] 318151 0
Measurement of plasma concentrations of RA101495 and its metabolites
Timepoint [4] 318151 0
Single Dose: Day 1 (pre-dose; 15 minutes; 1, 3, 6, 12 hours post dose), Day 2, 3, 5, 8, 15, 29.

Multiple Dose: Day 1-7 (pre-dose; 3, 6 hours post dose), Day 8, 15, 21, 35.

Eligibility
Key inclusion criteria
*Male or female, equal to, or greater than 18 and equal to or less than 65 years of age.
*Able to complete the informed consent procedure, including signing and dating the informed consent form.
*Females of childbearing potential must have a negative pregnancy test at Screening and within 24 hours prior to dosing of study drug.
*Females of childbearing potential and males must agree to use effective birth control. Effective contraception will begin at Screening for females and Day 1 for males, and will continue through Day 29 (28 days after dosing).
*Should have received vaccination against Neisseria meningitidis (at least two weeks
prior to dosing). Applies to subjects in single-dose cohorts 4 and 5 only and multiple dose
cohorts 6 and 7.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
*Positive throat swab for Neisseria meningitidis at Screening or a prior history of meningitis.
*Allergy to ciprofloxacin.
*Pregnant or nursing females.
*Body mass index < 18.0 kg/m2 or > 34.9 kg/m2.
*Surgery requiring general anesthesia within 3 months prior to Screening or during the study.
*Loss of > 500 mL of blood (by any process, including donation) within 3 months prior to Screening or blood donation during the study.
*Participation in any clinical trial and use of any investigational drug within 3 months prior to Screening.
*Use of systemic immune suppressive or immune stimulatory prescription drugs within one month prior to Screening.
*Use of any prescription or over-the-counter medication (excludes contraceptive pill) within 7 to 14 days prior to Screening, unless approved by both the investigator and the Sponsor.
*Positive test for hepatitis B surface antigen or for antibody to either human immunodeficiency virus-1 or human immunodeficiency virus-2 or hepatitis C virus.
*Diagnosis of any systemic infection within 6 months of screening.
*History of a malignancy within the past 10 years, evidence of, or required treatment for, cancer (except treated basal or squamous cell carcinoma of the skin or cured cervical carcinoma-in-situ).
*Screening laboratory test results that are abnormal in the opinion of the principal investigator (tests with abnormal results may be repeated once).
*Calculated creatinine clearance of < 80 mL/min (based on the Cockcroft-Gault equation).
*Confirmed, clinically significant abnormalities on electrocardiogram (tests with abnormal findings may be repeated once).
*Diagnosis of significant medical disease (chronic or active within the past 6 months), including, but not limited to: cardiac disease (e.g., unstable angina, myocardial infarction, congestive heart failure, ventricular arrhythmia), uncontrolled seizure disorder, liver disease, chronic infection (e.g., tuberculosis), or uncontrolled diabetes; diseases judged by the investigator as not clinically significant or as fully resolved will be reviewed with the Sponsor.
*Clinically significant abnormal findings on vital signs or physical examination (findings judged by the investigator as not clinically significant will be reviewed with the Sponsor).
*Use of any recreational drugs within 3 months prior to Screening.
*Unable or unwilling to comply with the requirements of the study in the judgment of the investigator.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
When all subjects in a single-dose dose cohort have completed the Day 5 visit, the Sponsor and the investigator(s) will review the available safety data. In the multiple-dose cohort, safety will be reviewed during the dosing period, after Day 8 and Day 15. If 2 or more subjects administered RA101495 in a dose cohort experienced a dose-limiting toxicity, then escalation to the next dose level will not proceed. The Sponsor and the investigator together may choose one of the following alternative actions:
*De-escalate, i.e., initiate an additional cohort either at the prior dose level or at an intermediate dose between the current and prior levels
*Terminate the study

If dose escalation is permissible, then based on the review of the data, the Sponsor and the investigator may choose one of the following actions:
*Escalate to the next planned dose level
*Escalate to an intermediate dose below the next planned level
*Repeat one of the completed dose levels
*Terminate the study
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 4439 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 10648 0
3181 - Prahran

Funding & Sponsors
Funding source category [1] 292193 0
Commercial sector/Industry
Name [1] 292193 0
Ra Pharmaceuticals, Inc.
Address [1] 292193 0
One Kendall Square
Suite B14301
Cambridge, MA 02139
Country [1] 292193 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services Pty Ltd
Address
Level 4, 88 Jephson St, TOOWONG QLD 4066
Country
Australia
Secondary sponsor category [1] 290871 0
Commercial sector/Industry
Name [1] 290871 0
Ra Pharmaceuticals, Inc.
Address [1] 290871 0
One Kendall Square
Suite B14301
Cambridge, MA 02139
Country [1] 290871 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293666 0
Alfred Hospital Ethics Committee (EC00315)
Ethics committee address [1] 293666 0
Commercial Road
Prahran, VIC 3181
Ethics committee country [1] 293666 0
Australia
Date submitted for ethics approval [1] 293666 0
21/09/2015
Approval date [1] 293666 0
10/11/2015
Ethics approval number [1] 293666 0
489/15

Summary
Brief summary
This is a first in human, randomized, placebo-controlled, double-blind, single dose, escalating dose and Multiple-Dose study of the safety and pharmacokinetics of RA101495 in healthy volunteers to evaluate safety of RA101495. There will be up to 5 single dose cohorts with doses of 0.05, 0.10, 0.20, 0.40 and 0.80 mg/kg. There will be up to 2 multiple dose cohorts with doses of 0.20 and 0.40 mg/kg. Study drug will be administered on Day1 for single dose cohorts and on Day1-7 for multiple dose cohorts as a single SC injection and the amount of drug given will depend on the dose of the cohort and the weight of the subject. Each cohort will be dosed a minimum of 7 days for single days cohorts and 14 days for multiple dose cohorts after the first subject in the previous cohort received the last dose. If 2 or more subjects administered RA101495 in a dose cohort experience a dose-limiting toxicity, dose administration in that cohort will stop and escalation to the next dose level will not proceed.
Trial website
Trial related presentations / publications
Johnston JM, Ricardo A, Arata M, Lickliter J, et.al. A Phase 1 Single-ascending-dose Clinical Study of RA101495, a Subcutaneously Administered Synthetic Macrocyclic Peptide Inhibitor of Complement C5 for Treatment of Paroxysmal Nocturnal Hemoglobinuria. EHA 2016 (Abstract P632)

Johnston JM, Ricardo A, Arata M, Lickliter J, et al. A Phase 1 Multiple-dose Clinical Study of RA101495, a Subcutaneously Administered Synthetic Macrocyclic Peptide Inhibitor of Complement C5 for Treatment of Paroxysmal Nocturnal Hemoglobinuria. EHA 2016 (Abstract LB2249)
Public notes

Contacts
Principal investigator
Name 60898 0
Dr Jason Lickliter
Address 60898 0
Nucleus Network
L5; Burnet Institute
AMREP Precinct
89 Commercial Road
Prahran, VIC 3181
Country 60898 0
Australia
Phone 60898 0
+61 3 9076 8960
Fax 60898 0
Email 60898 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 60899 0
Ms Beth Newstat
Address 60899 0
One Kendall Square
Suite B14301
Cambridge, MA 02139
Country 60899 0
United States of America
Phone 60899 0
+1 617 401 4073
Fax 60899 0
Email 60899 0
bnewstat@rapharma.com
Contact person for scientific queries
Name 60900 0
Dr Jeffrey M. Johnston, MD FACP
Address 60900 0
One Kendall Square
Suite B14301
Cambridge, MA 02139
Country 60900 0
United States of America
Phone 60900 0
+1 617 209 4060
Fax 60900 0
Email 60900 0
jjohnston@rapharma.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary